1. Field of the Invention
The cephalosporin derivatives of the present invention possess in general the usual attributes of that family of anti-bacterial agents and are particularly useful in the treatment of bacterial infections by injection.
2. Description of the Prior Art
Derivatives of various .alpha.-amino penicillins and cephalosporins with nitro-substituted heterocyclic aldehydes are described in U.K. patent specification No. 1,311,498. Reaction products of various .alpha.-amino penicillins and/or cephalosporins with formaldehyde are disclosed in South African Pat. No. 72/8475 (see U.K. patent specification No. 1,401,285), with acetaldehyde in South African Pat. No. 72/8474 (See U.K. patent specification No. 1,389,540) and with various aldehydes and ketones in South African Pat. No. 72/8476 (See U.K. patent specification No. 1,388,400).
Derivatives of cephalosporins having in the acylamido group at the 7-position an .alpha.-amino group which has been reacted with an aldehyde are disclosed in U.S. Pat. Nos. 3,880,842; 3,887,546 and Farmdoc 49804W.
The reaction products of acetone with various .alpha.-amino cephalosporins are disclosed in the patent literature as follows:
(1) with cephaloglycin, in U.S. Pat. No. 3,303,193; PA1 (2) with cephalexin, in U.S. Pat. No. 3,714,146 and U.K. patent specification No. 1,314,758 and U.S. Pat. No. 3,780,028; PA1 (3) with 7-[.alpha.-amino-(2'-thienyl)acetamido]-cephalosporanic acid, in U.S. Pat. No. 3,311,621; PA1 (4) with certain ring-substituted cephaloglycins in U.S. Pat. No. 3,464,985; and PA1 (5) with certain ring-substituted cephalexins and cephaloglycins, in U.S. Pat. Nos. 3,489,750; 3,489,751 and 3,489,752. PA1 R.sup.1 is hydrogen, sodium or potassium, PA1 R.sup.2 is carboxyl or 2-furyl or an aliphatic, aromatic or heterocyclic radical to which there is also attached a strongly acidic group in the form of its sodium or potassium salt, and PA1 R.sup.3 is tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-3-yl or 1,2,4-triazol-5-yl, each of such groups being unsubstituted or substituted with one or two lower alkyl groups of one to four carbon atoms. In the preferred embodiments the carbon atom attached to the benzene ring (para to the hydroxyl group) has the D configuration. PA1 R.sup.1 is hydrogen, sodium or potassium, PA1 R.sup.2 is carboxyl or 2-furyl or an aliphatic, aromatic or heterocyclic radical to which there is also attached a strongly acidic group in the form of its sodium or potassium salt, and PA1 R.sup.3 is tetrazol-5-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-3-yl or 1,2,4-triazol-5-yl, each of such groups being unsubstituted or substituted with one or two lower alkyl groups of one to four carbon atoms which comprises
More distantly related are the intermediates produced when a cephalosporin nucleus, e.g. 7-ACA or 7-ADCA, is acylated with a reactive derivative of an .alpha.-amino acid in which the .alpha.-amino group has been protected by prior reaction with a .beta.-diketo compound such as methyl acetoacetate, methyl acetoacetamide or acetylacetone; these are exemplified by Farmdoc 22850W and 60669V.
In the penicillin field the penicillins containing an .alpha.-amino group in the 7-acylamido substituent, e.g. ampicillin, with ketones and aldehydes were apparently first disclosed by Johnson et al. (U.S. Pat. No. 3,198,804) and Granatek (U.S. Pat. No. 3,198,788). Similar reaction products made from various such penicillins by reaction with the same or different aldehydes and ketones were later reported in U.S. Pat. Nos. 3,230,214, 3,316,247 (diketones), 3,325,479 (diketones), 3,489,746, 3,549,746, 3,558,602, 3,635,953, 3,641,000, 3,647,781 (which includes some cephalosporins), 3,725,389, 3,780,028, 3,784,562 (diketone), 3,886,140, 3,888,848, 3,905,955 and 3,904,604 and U.K. patent specification No. 1,267,936.